According to the World Health Organization's (WHO) fact sheet on Cardiovascular Diseases (CVDs), CVDs are the number one cause of death globally. (Fact Sheet No. 317, September 2012 accessed at www.who.int/mediacentre/factsheets/fs317/en/index.html on Jan. 31, 2013. The WHO estimates that an estimated 17.3 million people died from CVDs in 2008, representing 30% of all global deaths. Of these deaths, an estimated 7.3 million were due to coronary heart disease (CHD) and 6.2 million were due to stroke. The WHO also estimates that by 2030, almost 25 million people will die from CVDs, mainly from heart disease and stroke. The Global Burden of Disease Study estimates that the developing countries contributed 3.5 million of the 6.2 million global deaths from CHD in 1990. (Murray C J L and Lopez A D. The Global Burden of Disease A Comprehensive Assessment of Mortality and Disability from Disease, Injuries and Risk Factors in 1990 and Projected to 2020. Boston, Mass. Harvard University Press; 1996). The projections estimate that these countries will account for 7.8 million of the 11.1 million deaths due to CHD in 2020. The developed countries are not immune to CHD. For example, in the USA and Europe, CHD remains the largest single cause of death and disability. In 2005, CHD caused approximately 1 of every 5 deaths in the USA. (Heron M P, et. al. Deaths preliminary data for 2006. Natl. Vital. Stat. Rep. 2008; 56:1-52.) According to the Centers for Disease Control and Prevention it is the leading cause of death in America. Approximately 37% of people who develop a coronary event in a given year will die from it. While major reductions in CVD related mortality have been achieved in Europe, CVD still accounts for 54% of all deaths in women and 43% of all deaths in men.
CVD is associated with many risk factors. Of these risk factors, hyperlipidemia (e.g., hypertriglyceridemia) and hypercholesterolemia are significant indicators of CVD. As such, dietary supplements, nutraceuticals, and prescribed drugs containing Omega-3 fatty acid esters, such as the ethyl esters of EPA and DHA, are currently used for the treatment of CVD and, in particular, for the reduction of elevated triglycerides.
However, administration of dietary supplements, nutraceuticals, and prescribed drugs containing Omega-3 fatty acid esters presents significant challenges. For example, current dietary supplements, nutraceuticals, and prescribed drugs containing Omega-3 fatty acid esters have variable absorption and efficacy when orally administered. In particular, current compositions have a pronounced “food effect,” with poor absorption when taken while fasting or with a low fat meal. When taken with fatty foods, the absorption of Omega-3 fatty acid esters improves, due in part to the presence of bile salts that are released in the intestines, which aid absorption of Omega-3 fatty acid esters.
To overcome low absorption, patients can be dosed with compositions having greater amounts of Omega-3 fatty acid esters, but there are practical limitations to this approach due to the side effects that are commonly associated with such compositions. The oxidative degradation of Omega-3 fatty acid esters that occurs over time can result in an unpleasant aftertaste following administration, especially when consumed in large quantities. Burping and stomach upset are further unpleasant side effects associated with the consumption of Omega-3 fatty acid esters. Following consumption, Omega-3 fatty acid esters tend to float on top of liquid contents in the stomach, forming a layer that prevents the passage of small gas bubbles. When sufficient gas has built up to overcome the surface tension of the oil layer, a person burps. The burps usually contain a fishy taste and smell.
Accordingly, side effects associated with the administration of current compositions comprising Omega-3 fatty acid esters (e.g., susceptibility to the food effect, large doses to attain efficacy, and the resulting aftertaste, unpleasant smell, and burping) are known to significantly reduce patient compliance.
While practicing a healthy lifestyle may reduce the incidence of CVD, new therapeutic approaches to manage CVD are warranted. These new approaches might include the discovery of new drugs or improve upon current medications used to treat CVD. The discovery of new drugs, however, comes at a high price with no certainty of eventual success. Accordingly, new or more efficient ways of delivering current medications with a proven safety and efficacy profile should be developed. Thus, there is a need for improved compositions comprising Omega-3 fatty acid esters, such as the ethyl esters of EPA and DHA, that are less susceptible to food effect and which attain high efficacy at lower doses. Ideally, such improved compositions would minimize or eliminate an unpleasant smell and/or an unpleasant aftertaste, and/or burping in the patient. Such an improved composition with reduced side effects would improve patient compliance and more effectively treat the risk factors related to cardiovascular disease.
However, the administration of Omega-3 fatty acid esters alone may not be sufficient to manage CVD in certain patient populations. Such patients may require administration of additional medications to assist in improving their blood lipid profiles. Additional treatment options can include co-administration of other lipid regulating medications, such as for example, statins or fibrates, that act to lower low density lipoprotein (LDL) cholesterol, and concomitantly APO-B and/or triglycerides (TG). Unfortunately, patient compliance suffers when a patient is required to take several different medicines, sometimes several times a day, in order to achieve the optimal blood serum lipid profile. It would be ideal if patients in need of multiple medications could be prescribed a unitary pharmaceutical dosage form comprising multiple actives for managing CVD. The manufacture of such dosage forms, however, poses a challenge—the stability and other physicochemical properties of one active may be affected by another different active. Accordingly, there is a need for improved pharmaceutical compositions that comprise more than one active for the treatment of CVD in a unitary pharmaceutical dosage form. Optimally, such compositions should reduce blood serum TG levels, lower LDL, and optionally increase high density lipoprotein (HDL) cholesterol. EPA and DHA represent viable treatment options for patients with elevated TG levels. Thus far, the FDA has approved an Omega-3 fatty acid composition comprising EPA ethyl ester and DHA ethyl ester (LOVAZA®; GlaxoSmithKline, Research Triangle Park, N.C. 27709. LOVAZA® was approved by the US FDA on Nov. 10, 2004. Application No. N021654. See US FDA Orange Book for Approved Drug Products with Therapeutic Equivalence Evaluations) and a composition comprising EPA only (VASCEPA®; Amarin Corporation plc, Dublin, Ireland. VASCEPA® was approved by the US FDA on Jul. 26, 2012. Application No. N202057. See FDA Orange Book for Approved Drug Products with Therapeutic Equivalence Evaluations). These medications may lower TG levels, but they may also increase LDL cholesterol levels. While there are no data suggesting that increases in LDL-C associated with Omega-3 fatty acid formulations lead to adverse outcomes, these increases in LDL-C may prevent the attainment of optimal lipid profiles in patients suffering with CVD. Thus, there is an unmet need for pharmaceutical compositions that can lower TG levels without increasing LDL cholesterol levels. Combination therapy, in a unitary pharmaceutical dosage form, comprising the Omega-3 fatty acids EPA and DHA together with a non-Omega-3 lipid-lowering and/or cholesterol-lowering agent may meet this need.